PROJECT SUMMARY ANIMAL MODEL PRODUCTION CORE The overall goal of the Somatic Cell Editing Consortium (SCGE) is to create a novel, integrated set of genome editing tools to accelerate translation of these approaches to the clinic. The goal of the JAX Gene Editing Mouse Testing Center (JAX-GEMTC) is to provide a robust, scalable platform for the optimization and credentialing of new editing machinery. Reporter models designed to detect different types of specific and non- specific genome-editing activity are essential for the systematic and efficient evaluation of a variety of novel delivery approaches designed to target a diverse array of disease-relevant cells and tissues. The specific goals of the Animal Model Production component of this Center are to generate and validate a suite of genome- editing reporter mouse lines that will illustrate the efficiency, specificity, and nature of editing modifications with single-cell resolution, and to develop a platform for future reporter line development to serve the goals of SCGE consortium members. Building on our existing reporter model, we will create a panel of reporter lines that support analysis of multiple editors, editing outcomes, and off-target activity. Through the colony management and distribution effort of the RESOURCE CORE, these models will serve to support the goals of the TESTING CORE. Our goals will be achieved through three Specific Aims: 1) We will generate mouse reporter lines designed to test somatic cell editing efficiency and specificity for multiple types of editing activity, including NHEJ-mediated indels, HR, base editing, and off-target activity; We will assess the function of each reporter line in vivo to assure its utility as a test platform for new delivery technologies; 3) To develop and deploy platforms and models to support future collaborations with the SCGE consortium. To accomplish this, we will validate and implement a novel recombinase-mediated cassette exchange (RMCE) platform to improve the efficiency of targeting of large reporter constructs, and will work with the SCGE to develop reporter models that assess novel editor functions not captured by the panel of lines produced in Aim 1.